MACROCYTIC ANEMIAS
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These are the anemias in which the RBC have an MCV of greater than 100fl
There are 2 groups of macrocytic anemias
Megaloblastic anemia
Non megaloblastic macrocytic anemia
Requirements for Red Blood Cell Production
 Erythropoeitin
 Proteins, required for globin synthesis
 Iron
 Vitamin B12 and folic acid
 Vitamin B6
 Vitamin C
 Thyroid hormones, estrogens and androgens
MEGALOBLASTIC ANEMIA
 These are a group of disorders in which the cause the anemia is due to
deficiency of vitamin B12 and folic acid
 The macrocytes in this condition is usually “oval” - hence they are also
called as MACRO OVALOCYTES
NON MEGALOBLASTIC MACROCYTIC ANEMIAS
 These are disorders in which the macrocytosis is not due to vitamin B12 or
folic acid deficiency
 Here the macrocytes are “ROUND”
 The conditions in which such round macrocytes are seen are
1. Reticulocytosis
2. Hypothyroidism / myxedema
3. Myelodysplastic syndrome
4. Scurvy
5. Sideroblastic anemia
6. Liver disorders
 Vitamin B12 and folic acid are important nutrients required in the process of
nuclear maturation
 They are required during erythropoiesis during DNA synthesis
 These anemias may be caused because of a nutritional deficiency or impaired
absorption mainly.
 Impaired DNA synthesis leading to defective cell maturation and cell division
 Nuclear maturation lags the cytoplasmic maturation – NUCLEAR
CYTOPLASMIC ASYNCHRONY
 Abnormally large erythroid precursors and red cells
 Affect all marrow elements.
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 Neurologic symptoms (dorsal columns)
 Ineffective erythropoiesis:
High indirect bilirubin
Very high LDH
Folic Acid:
– It is a vitamin which yellow in colour, water soluble, necessary for the
production of the RBC, WBC and platelets.
– It is not synthesized in the body.
– It is found in large number of green fresh vegetables, fruits.
Daily requirement:
The human body needs about 100-150 µg daily.
Absorption:
It is absorbed in the Duodenum and Jejunum.
Transportation:
Weakly bound to albumin.
METABOLIC FUNCTION
1. Purine synthesis
2. Conversion of homocysteine to methionine ( which also requires B12 )
3. Deoxythymidilate synthesis.
FOLIC ACID DEFICIENCY
1. INCREASED DEMAND
2. DECREASED INTAKE
3. DECREASED ABSORPTION
4. METABOLIC INHIBITION
INCREASED DEMAND
 Pregnancy
 Lactation
 Infancy
 Puberty and growth period
 Patients with chronic hemolytic anemias
 Disseminated cancer
DECREASED INTAKE
 Elderly
 Lower socio economic status
 Chronic alcoholics
DECREASED ABSORPTION
 Acidic food substances in foods like legumes, beans
 Drugs like phenytoin, oral contraceptives
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 Celiac disease which affect the gut absorption
 Heat sensitive – more loss during cooking
METABOLIC INHIBITION
VITAMIN B12
 This vitamin is synthesized in nature by micro-organism in the intestine of
man and animals, but we can not obtain it from the bacteria in our bodies,
because it is synthesizing in the large colon after the site of absorption and
it is wasted in the faeces in about 5µg/day. So we obtain it from animal
food such as liver, kidney, meat and dairy products as milk and cheese.
 Abundant in animal foods
 Microorganisms are the ultimate origin of cobalamin
 It is stored in liver for many years
 It is efficiently reabsorbed from bile
 It is resistant to cooking and boiling
 Diary requirements:
The human body needs about 1-2 µg daily.
 Absorption:
B12 is combined with glycoprotein called the intrinsic factor (IF), which is
synthesized in the gastric cells. The absorption occurs in the distal ileum.
 Transportation:
Transport by a protein synthesized in the liver called Transcobalamine II, which
carry vitamin B12 to liver, nerves and bone marrow.
VITAMIN B12 DEFICIENCY
1. INCREASED REQUIREMENT
2. DECREASED INTAKE
3. IMPAIRED ABSORPTION
INCREASED DEMAND
a. Pregnancy
b. Lactation
c. Puberty
d. Growth period
e. Hyperthyroidism
f. Disseminated cancer
DECREASED INTAKE
a. Inadequate intake
b. Vegetarian diet
IMPAIRED ABSORPTION
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 INTRINSIC FACTOR DEFICIENCY due to chronic gastritis or antibodies
against stomach cells.
- PERNICIOUS ANEMIA
- GASTRECTOMY
 Malabsorption states
 Diffuse intestinal diseases. Eg., lymphoma, systemic sclerosis
 Competitive parasitic uptake – fish tapeworm
 Bacterial overgrowth
CLINICAL FEATURES
1. Patients develop all general symptoms and signs of the anaemia.
2. Knuckle pigmentation
3. Angular stomatitis
4. Atrophic glossitis- “beefy” tongue
5. Neurological disorders: sever deficiency of the folic acid causes neuropathies
diseases.
6. Deficiency during pregnancy causes neural tube defect.
PERIPHERAL BLOOD FINDINGS
1. Hemoglobin – decreased
2. Hematocrit – decreased
3. RBC count – decreased/normal
4. MCV - >100fl ( normal 82-98fl)
5. MCH –increased
6. MCHC – NORMAL
7. Reticulocytopenia.
8. Total WBC count – normal / low
9. Platelet count – normal/ low
10.Pancytopenia, especially if anaemia is sever.
PERIPHERAL SMEAR OR STAINED BLOOD FILM
 RBC:
 -Poikilocytosis - tear drops and schistocytes
 Anisocytosis - oval macrocytes
- Macro ovalocytes (macrocytic normochromic)
- Well hemogloibised, thicker than normal
- Inclusions like HOWELL JOLLY BODIES, basophilic stippling, Cabot rings
 WBC:
Normal count or reduced count
Hypersegmented neutrophils (>5 lobes)
MACRO POLYMORPHO NUCLEAR CELLS (Macropolys)
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 PLATELETS:
Normal or decreased
BONE MARROW
 Markedly hypercellular
 Myeloid : erythroid ratio decreased or reversed. (Normally, there are three
myeloid precursors for each erythroid precursor resulting in a 3:1 ratio,
known as the M:E (myeloid to erythroid) ratio)
 Erythropoiesis : MEGALOBLASTIC
MEGALOBLAST
1. Abnormally large precursor
2. Deeply basophilic royal blue cytoplasm
3. Fine chromatin with prominent nucleoli
4. Nuclear cytoplasmic asynchrony
5. Abnormal mitoses
6. Maturation arrest
BIOCHEMICAL FINDINGS
 Increase in serum unconjugated bilirubin- because of ineffective
erythropoiesis
 Increase is LDH
 Normal serum iron and ferritin
TESTS FOR FOLATE AND B12 DEFICIENCY
 Serum folate assay
 Red cell folate assay
 Serum B12 assay
PERNICIOUS ANEMIA
 Scandinavian countries more prevalent
 Disease of elderly – 5th to 8th decades
 Genetic predisposition
 Tendency to form antibodies against multiple self antigens
PATHOGENESIS
 Immunologically mediated, autoimmune destruction of gastric mucosa
 CHRONIC ATROPHIC GASTRITIS – marked loss of parietal cells
 Three types of antibodies
a) Type I antibody- 75% - blocks vitamin B12 and IF binding
b) Type II antibody – prevents binding of IF-B12 complex with ileal receptors
c) Type III antibody – 85-90% patients – against specific structures in the
parietal cell
 Associated with other autoimmune diseases like autoimmune thyroiditis
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DIAGNOSTIC FEATURES
1. Moderate to severe megaloblastic anemia
2. Leucopenia with hypersegmented neutrophils
3. Mild to moderate thrombocytopenia
4. Mild jaundice due to ineffective erythropoiesis and peripheral hemolysis
5. Neurologic changes
6. Low levels of serum B12
7. Elevated levels of homocysteine
8. Striking reticulocytosis after parenteral administration of vitamin B12
9. Serum antibodies to intrinsic factor
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